Three-dimensional pharmacophore mapping of certain anticancer alpha-methylene-gamma-butyrolactones.

A definition of pharmacophore hypotheses for certain anticancer alpha-methylene-gamma-butyrolactones was carried out by consideration of a three-dimensional model that correlates the chemical structures of a series of alpha-methylene-gamma-butyrolactones with their cytostatic activity. Training sets consisting of 20 alpha-methylene-gamma-butyrolactones were selected in each case on the basis of the information content of the structures and the activity data as required by the HypoGen program in the Catalyst software. In this case, the best pharmacophore in terms of statistics and predictive value consisted of four features: two hydrogen bond acceptors (HBA), one hydrophobic (HP) feature, and one aromatic ring (AR) feature. The selected pharmacophore hypothesis yielded a correlation coefficient of 0.942 with a cost difference (null cost minus total cost) of 40.342. The pharmacophore was validated on a set of test compounds. This validation study provided confidence for the usefulness of the selected pharmacophore model to identify compounds with diverse structures from a database search. This investigation has demonstrated a practical approach toward the development of anticancer lead compounds through a three-dimensional pharmacophore mapping.